COMT is an enzyme which catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to the m-hydroxy group of catecholamine transmitters, their metabolites and L-dopa, thereby inactivating them. It is widely distributed in various cerebral and peripheral tissues of all mammalian species. In the cell, the occurrence of at least two distinct isomers of COMT has been demonstrated, of which one is soluble and the other membrane-bound. Although both forms of COMT catalyze the O-methylation of catecholamines, the relative abundance differs in various tissues and species.
Selective COMT inhibitors combined with L-dopa and a peripheral dopa decarboxylase inhibitor are expected to improve the availability and efficiency of L-dopa, by preventing its conversion to 3-O-methyldopa, in L-dopa therapy of Parkinson's disease. Some COMT inhibitors have been described earlier, but all of these have been ineffective, toxic or poorly selective for COMT. Recently, several new potent and selective COMT inhibitors have been developed and are presently under clinical trial for the treatment of Parkinson's disease.
The current situation prompted the inventors to search for further novel COMT inhibitors. For the purpose of finding such novel compounds, the present inventors isolated a number of microorganisms organisms from soils and living things etc., from which the produced compound was purified for study. As the result, the present inventors found that some specific microorganisms produce the novel compound of formula I having a potent and selective COMT inhibiting activity.